EP1061926A2 - Heterocyclic compounds, their production and use as tachykinin receptor antagonists - Google Patents

Heterocyclic compounds, their production and use as tachykinin receptor antagonists

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Publication number
EP1061926A2
EP1061926A2 EP99909233A EP99909233A EP1061926A2 EP 1061926 A2 EP1061926 A2 EP 1061926A2 EP 99909233 A EP99909233 A EP 99909233A EP 99909233 A EP99909233 A EP 99909233A EP 1061926 A2 EP1061926 A2 EP 1061926A2
Authority
EP
European Patent Office
Prior art keywords
group
ring
membered
alkyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99909233A
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German (de)
English (en)
French (fr)
Inventor
Hideaki Natsugari
Takayuki Doi
Yoshinori Ikeura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Chemical Industries Ltd
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Publication date
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to EP01127194A priority Critical patent/EP1184036A2/en
Publication of EP1061926A2 publication Critical patent/EP1061926A2/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel utility of heterocyclic compounds having a tachykinin receptor antagonistic action, and novel heterocyclic compounds having such action, a method for producing them, as well as a pharmaceutical composition comprising the foregoing heterocyclic compounds.
  • EP-A-0733632 describes that a heterocyclic compound represented by the formula:
  • ring M is a heterocyclic ring
  • the present invention aims to provide a novel utility of the heterocyclic compound (I) or a salt thereof.
  • the present inventors have assiduously studied in consideration of the above-mentioned situation and, as a result , have found that the heterocyclic compound ( I ) shows a treating effect against depression, anxiety, manic- depressive illness or psychopathy. On the basis of these findings, the present inventors have completed the present invention.
  • the present invention relates to: (I) A pharmaceutical composition for preventing or treating depression, anxiety, manic-depressive illness or psychopathy which comprises a compound represented by the formula:
  • R a and R b are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M;
  • Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, with the proviso that at least one of them is an optionally substituted heterocyclic ring;
  • Ring C is an optionally substituted homocyclic or heterocyclic ring
  • Ring Z is an optionally substituted nitrogen-containing heterocyclic ring
  • n is an integer from 1 to 6 , or a salt thereof
  • a 5-membered to 9-membered cyclicamino group which may have 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to the nitrogen atom in the amino group and which may be substituted by C x _ 6 alkyl group,
  • R a and R b are bonded to each other to form Ring A, and the Ring A is
  • a 5-membered to 9-membered aromatic heterocyclic ring having 1 to 3 of hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms ( ⁇ ) a 5-membered to 9-membered non-aromatic heterocyclic ring having 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, or (iii) a 3-membered to 10-membered cyclic hydrocarbon, each of which may have 1 to 4 substituents selected from the group consisting of
  • a 5-membered to 9-membered cyclicamino group which may have 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to the nitrogen atom in the amino group,
  • Ring B is a (i) 5-membered to 9-membered aromatic heterocyclic ring having 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms ,
  • a 5-membered to 9-membered cyclicamino group which may have 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to the nitrogen atom in the amino group.
  • a C 1 . 6 alkyl-carbonylamino group
  • a 5-membered to 9-membered heterocyclic ring which has 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, optionally having 1 to 5 substituents selected from the group consisting of (1) a halogen atom,
  • a 5-membered or 6-membered aromatic monocyclic heterocyclic group which has 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms , optionally substituted by 1 to 3 optionally halogenated C ⁇ ,, alkyls , or (ii) a 3-membered to 10-membered cyclic hydrocarbon optionally having 1 to 5 substituents selected from the group consisting of
  • a mono- or di-C ⁇ alkylamino group (15) a mono- or di-C ⁇ alkylamino group.
  • a 5-membered to 9-membered cyclic amino group which may have 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to the nitrogen atom in the amino group,
  • ( 29 ) a 5-membered or 6-membered aromatic monocyclic heterocyclic group which has 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, optionally substituted by 1 to 3 optionally halogenated C ⁇ alkyls ;
  • the Ring Z is a 5-membered to 12-membered heterocyclic ring which may have at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to Y and the nitrogen atom, optionally having 1 to 5 substituents selected from the group consisting of
  • a 5-membered to 9-membered cyclic amino group which may have 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to the nitrogen atom in the amino group.
  • a 5-membered to 9-membered cyclicamino group which may have 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to the nitrogen atom in the amino group and, (i) a C 1 _ i alkylsulfonylamino group, (j) a C 1 _ 6 alkyl-carbonyloxy group and (k) a halogen atom, (3) a 5-membered to 9-membered (preferably 6-membered) cyclicamino group which may have 1 to 3 hetero atoms (preferably 1 or 2) selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to the nitrogen atom in the amino group and which may be substituted by C 1 . 6 alkyl group,
  • Ring A is a 5-membered to 9-membered aromatic heterocyclic ring which has 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms (preferably pyridine ring), optionally substituted by C _ 6 alkyl group; the Ring B is a C 6 .
  • aryl group (preferably benzene ring) which may be substituted by substituents selected from the group consisting of (i) a C x _ 6 alkyl group optionally substituted by a hydroxy group, (ii) a C x _ 6 alkylcarbonyl group (including formyl) and (iii) a carboxyl group; the Ring C is a C 6 .
  • Ring Z is a 5-membered to 12-membered heterocyclic ring which may have at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to Y and the nitrogen atom, optionally substituted by 1 to 3 substituents selected from the group consisting of (i) a C 1 . 6 alkyl group, (ii) a hydroxy group and (iii) an oxo group ;
  • R 1 is a C x _ 6 alkyl group
  • R 2 is a C ⁇ _ 6 alkoxy group, optionally halogenated C 1 _ 6 alkyl group, a halogen atom, a hydroxy group or C 7 .
  • X is 1 to 5 groups selected from the group consisting of a hydrogen atom, a C ⁇ _ 6 alkyl group and a halogen atom, provided that (1) when R 1 is a methyl group and R 2 is s trifluoromethyl group, X is a halogen atom, and (2) when R 1 is a methyl group and R 2 is a methoxy group, X is a hydrogen atom or a halogen atom,
  • R 1 is a C ⁇ _ 6 alkyl group
  • R 2 is a C 1 _ 6 alkoxy group, optionally halogenated C 1-6 alkyl group, a halogen atom, a hydroxy group or a C 7 .
  • X is 1 to 5 groups selected from the group consisting of a hydrogen atom, a C 1 _ 6 alkyl group and a halogen atom, provided that (1) when R 1 is a methyl group and R 2 is s trifluoromethyl group, X is a halogen atom and (2) when R 1 is a methyl group and R 2 is a methoxy group, X is a hydrogen atom or a halogen atom, or a salt thereof,
  • (X) A compound as defined in (IX) , wherein R 1 is a C ⁇ alkyl group, R 2 is a C ⁇ alkoxy group, optionally halogenated C ⁇ alkyl group, a halogen atom, a hydroxy group or a benzyloxy group, X is a hydrogen atom, or 1 or 2 groups selected from the group consisting of a C ⁇ alkyl group and a halogen atom,
  • composition for antagonizing a Substance P receptor which comprises a compound as defined in (IX),
  • composition for antagonizing a neurokinin A receptor which comprises a compound as defined in (IX),
  • XX A pharmaceutical composition for preventing or treating disorders of asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel syndrome or emesis, which comprises a compound as defined in (IX),
  • Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, with the proviso that at least one of them is an optionally substituted heterocyclic ring;
  • Ring C is an optionally substituted homocyclic or heterocyclic ring
  • Ring Z is an optionally substituted nitrogen-containing heterocyclic ring; and n is an integer from 1 to 6 , or a salt thereof for manufacturing a composition for preventing or treating depression, anxiety, manic-depressive illness or psychopathy, (XXII)
  • XXII A method for preventing or treating disorders of micturition in mammals which comprises administrating to a subject in need an effective amount of a compound represented by the formula:
  • Ring C is an optionally substituted homocyclic or heterocyclic ring
  • Ring Z is an optionally substituted nitrogen-containing heterocyclic ring
  • n is an integer from 1 to 6 , or a salt thereof
  • XXVI Use of a compound as defined in (IX) for manufacturing a pharmaceutical composition for treating disorders of micturition
  • (XXVII) Use of a compound as defined in (IX) for manufacturing a pharmaceutical composition for treating disorders of asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel syndrome or emesis, which comprises a compound as defined in (IX),
  • (XXVIII) A method for antagonizing a tachykinin receptor in mammals which comprises administrating to a subject in need, an effective amount of a compound as defined in (IX)
  • (XXIX) A method for antagonizing a Substance P receptor in mammals which comprises administrating to a subject in need an effective amount of a compound as defined in (IX), 17
  • (XXX) A method for antagonizing a neurokinin A receptor in mammals which comprises administrating to a subject in need an effective amount of a compound as defined in (IX),
  • (XXXI) A method for preventing or treating disorders of micturition in mammals which comprises administrating to a subject in need an effective amount of a compound as defined in (IX) , and
  • (XXXII) A method for preventing or treating disorders of asthma, rheumatoid arthritis , osteoarthritis, pain, cough, irritable bowel syndrome or emesis in mammals which comprises administrating to a subject in need an effective amount of a compound as defined in (IX).
  • a compound as defined in the above-mentioned (I) includes a compound of a formula (la):
  • heterocyclic compounds (I) used for the composition of the present invention are compounds disclosed in EP-
  • R a and R b are bonded to each other to form Ring A, or these are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M.
  • the substituents R a and R b on the Ring M include, for example, a halogen atom, an optionally substituted alkyl group, an optionally halogenated alkoxy group, an optionally halogenated alkylthio group, a cycloalkyl group, an aryl group, an acylamino group, an acyloxy group, a hydroxy group, a nitro group, a cyano group, an amino group , a mono- or di-alkylamino group, a cyclic amino group (e.g., a halogen atom, an optionally substituted alkyl group, an optionally halogenated alkoxy group, an optionally halogenated alkylthio group, a cycloalkyl group, an aryl group, an acylamino group, an acyloxy group, a hydroxy group, a nitro group, a cyano group, an amino group , a mono- or di-alky
  • a cyclic amino group optionally containing hetero atom(s) of oxygen atom, sulfur atom, etc., in addition to nitrogen atom
  • an alkylcarbonylamino group an alkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group, an alkylcarbonyl group, a carbamoyl group, a mono- or di- alkylcarbamoyl group, an alkylsulfonyl group, an oxo group, etc.
  • halogen atom includes, for example, fluorine, chlorine, bromine and iodine atoms.
  • the halogen atom includes, for example, fluorine, chlorine and bromine atoms.
  • the "optionally substituted alkyl group” includes, for example, C ⁇ alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups , etc.) optionally having from 1 to 5 substituents selected from a hydroxy group, a C ⁇ alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, etc.), a C 1 .
  • C ⁇ alkyl groups e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups , etc.
  • substituents selected from a hydroxy group
  • a C ⁇ alkoxy group e.g., methoxy, ethoxy, propoxy, butoxy, is
  • alkylthio group e.g., methylthio, ethylthio, propylthio, butylthio, isobutylthio, sec- butyltio, tert-butyltio, etc.
  • an amino group e.g., a C 1 . 1 acylamino group (e.g. formylamino , acethyl amino , propyonyl amino, butylyl amino, benzoyl amino, etc. )
  • an N-alkylamino group a carboxyl group, a nitro group, a mono- or di-C ⁇ alkylamino group (e.g.
  • N-substituted amino group substituted by one or two homocyclic groups e.g., mono- or di- C 3 . 8 cycloalkylamino groups , for example , cyclopropylamino , cyclobutylamino , cyclohexylamino ; C 6 .
  • arylamino groups for example, phenylamino, etc.
  • an optionally substituted heterocyclic groups e.g., 5-membered to 9-membered cycloamino groups which may have 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms (e.g., 5-membered or 6-membered non-aromatic cycloamino groups, for example, piperidyno, 4-methylpiperodyno, morpholino, thiomorpholino , piperadinyl, 4-methylpiperadinyl, 4- ethylpiperadinyl , pyrrolidinyl, imidazolydinyl, pyrazolydinyl; 5-membered or 6-membered aromatic cycloamino groups , for example , pyridyl , pyradyl , pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazuly
  • C x _ 4 alkylsulfonylamino groups for example, methylsulfonylamino , ethylsulfonylamino , etc.
  • a C ⁇ alkyl-carbonyloxy group e.g., acetoxy and ethylcarbonyloxy groups, etc.
  • a halogen atom e.g., fluorine, chlorine and bromine atoms, etc.
  • the "optionally substituted alkyl group” includes C 1 . 6 alkyl groups optionally substituted by 1 to 4 halogen atoms, especially optionally halogenated C 1-4 alkyl groups (e.g., C ⁇ alkyl groups and C 1 .
  • alkyl groups substituted by 1 to 3 halogen atoms, etc. such as methyl, chloromethyl , fluoromethyl, difluoromethyl , trichloromethyl , trifluoromethyl , ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2 , 2 , 2-trifluoroethyl, pentafluoroethyl, propyl, 3 , 3 , 3-trifluoropropyl, isopropyl, 1- (trifluoromethyl)ethyl, butyl, 4,4,4- trifluorobutyl, isobutyl, sec-butyl and tert-butyl groups, etc.
  • halogen atoms etc.
  • C ⁇ _ 6 alkoxy-Ci.g alkyl groups e.g. C ⁇ ,, alkoxy-C ⁇ alkyl groups, for example, methoxymethyl , ethoxymethyl, isopropoxymethyl , butoxymethyl, methoxyethyl, ethoxyethyl, etc.
  • C 1 _ 6 alkyltho-C ⁇ alkyl groups e.g.
  • C x _ 4 alkylthio-C ⁇ alkyl groups for example, methylthiomethyl, ethylthiomethyl, butylthiomethyl , methylthioethyl , ethylthioethyl, etc.
  • amino -C ⁇ _ 6 alkyl groups preferably, amino-Ci. 4 alkyl groups
  • C 1 _ 1 acylamino -C 1 _ 6 alkyl groups e.g.
  • C ⁇ acylamino-C ⁇ alkyl groups for example, formylaminomethyl, acetylaminomethyl , propionylaminomethyl, butylylaminoethyl , benzoylaminomethyl, etc.
  • alkyl groups e.g.
  • alkyl groups for example, methylaminomethyl , ethylaminomethyl , butylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-(N-methylamino)ethyl, 2- (N-ethylamino)ethyl, 2-(N- methylamino)propyl, 3- (N-methylamino)propyl, 3-(N- methylamino)butyl , 4- (N-methylamino)butyl, 2-(N- dimethylamino)ethyl , 2- (N-dimethylamino)ethyl groups, C 3 .
  • cycloalkylamino-Ci.g alkyl groups e.g. C 3 . 10 cycloalkylamino-C 1 . 4 alkyl groups, for example, cyclopropylaminomethyl, cyclobutylaminomethyl , cyclohexylaminomethyl , cyclopropylaminomethyl , cyclobutylaminomethyl , cyclohexylaminomethyl , phenylaminomethyl, etc.
  • 5-membered or 6-membered non- aromatic cycloamino optionally having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addtion to carbon atoms-C ⁇ alkyl groups (e.g.
  • 5-membered or 6- membered non-aromatic cycloamino-C ⁇ alkyl groups for example, piperidinomethyl, 4-methylpiperidinomethyl, morpholinomethyl, thiomorpholinomethyl, piperadinylmethyl, 4-methylpiperadinylmethyl , piperidinoethyl , morpholinoethyl , piperadinylethyl; 5-membered or 6- membered aromatic cycloamino-C ⁇ , alkyl groups, for example, pyridylmethyl , pyrimidinylmethyl , imidazolylmethyl , pyridylethyl , etc.), C 1 _ 6 alkyl groups (e.g.
  • C ⁇ alkyl-carbonyloxy-C ! ⁇ alkyl groups for example, methylcarbonyloxymethyl , ethylcarbonyloxymethyl , butylcarbonyloxymethyl, methylcarbonyloxye
  • the "optionally halogenated alkoxy group” includes, for example, C 1 . 6 alkoxy groups or C ⁇ alkoxy groups substituted by 1 to 5 halogen atoms , etc .
  • Such alkoxy groups or halogenated alkoxy groups include, for example, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy , ethoxy, 2 , 2, 2-trifluoroethoxy, 2,2,2- trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4, 4, 4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy and hexyloxy groups, etc.
  • the "optionally-halogenated alkoxy group” includes C- ⁇ alkoxy groups or C 1-4 alkoxy group substituted by 1 to 3 halogen atoms , for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2, 2, 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4, 4, 4-trifluorobutoxy, isobutoxy and sec-butoxy groups, etc.
  • the "optionally halogenated alkylthio group” includes, for example, C x _ 6 alkylthio groups, and x _ 6 alkylthio groups having 1 to 5 halogen atoms, etc.
  • alkylthio groups and halogenated alkylthio groups include, for example, methylthio, difluoromethylthio, trifluoromethylthio , ethylthio, propylthio, isopropylthio, butylthio, 4,4,4- trifluorobutylthio , pentylthio and hexylthio groups, etc.
  • the "optionally halogenated alkylthio group” includes C ⁇ ,, alkylthio groups, or C ⁇ alkylthio groups substituted by 1 to 3 halogen atoms , for example, methylthio , difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio and 4,4,4- trifluorobutylthio groups, etc.
  • the "cycloalkyl group” includes C 3 . 10 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl groups, etc.);
  • the "aryl group” includes C 6 . 10 aryl groups (e.g. , phenyl group, etc.);
  • the "acylamino group” includes, for example, C ⁇ acylamino groups (e.g. , formylamino , acetylamino , propionylamino, butyrylamino and benzoylamino groups, etc.), etc.
  • acyloxy group includes, for example, C ⁇ acyloxy groups (e.g., formyloxy, acetoxy and propionyloxy groups, etc.), etc.
  • the "mono- or di-alkylamino group” includes, for example, mono- or di-C ⁇ alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino and diethylamino groups, etc.), etc.
  • the "cyclic amino group” includes, for example, 5-membered to 9-membered cyclic amino groups optionally having from 1 to 3 hetero atoms, such as oxygen atom, sulfur atom, etc., in addition to nitrogen atom (e.g., pyrrolidino, piperidino, morpholino and thiomorpholino groups, etc.), etc.
  • the "alkylcarbonylamino group” includes, for example, C ⁇ alkyl-carbonylamino groups (e.g., acetylamino, propionylamino and butyrylamino groups , etc . ) ; the "alkylsulfonylamino group” includes, for example, C x .
  • alkylsulfonylamino groups e.g., methylsulfonylamino and ethylsulfonylamino groups, etc.
  • alkoxycarbonyl group includes, for example, C x _ 4 alkoxy-carbonyl groups (e.g. , methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl and butoxycarbonyl groups, etc.
  • alkylcarbonyl group includes, for example, C ⁇ alkylcarbonyl groups (e.g., formyl, methylcarbonyl, ethylcarbonyl and propylcarbonyl groups, etc.);
  • the "mono- or di-alkylcarbamoyl group” includes for example, mono- or di-C ⁇ ,, alkylcarbamoyl groups (e.g., methylcarbamoyl , ethylcarbamoyl , dimethylcarbamoyl and diethylcarbamoyl groups, etc.);
  • alkylsulfonyl group includes, for example, C ⁇ alkylsulfonyl groups (e.g.
  • Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, and at least one of these is an optionally substituted heterocyclic ring.
  • the "homocyclic or heterocyclic ring” includes, for example, (i) an aromatic heterocyclic ring or non-aromatic heterocyclic ring having the same one or different hetero atoms selected from nitrogen, sulfur and oxygen atoms, preferably from 1 to 3 such hetero atoms , in addition to carbon atoms, or (ii) a cyclic hydrocarbon ring (homocyclic ring) consisting of carbon atoms, etc.
  • aromatic heterocyclic ring includes, for example, 5-membered or 6-membered aromatic heterocyclic rings having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms , in addition to carbon atoms (e.g. , pyridine , pyrazine , pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings, etc.), etc.
  • the aromatic heterocyclic ring includes , for example, pyridine, pyrazine and thiophene rings, etc., as well as pyrrole and thiazole rings, etc.
  • pyridine pyrazine and thiophene rings
  • pyrrole and thiazole rings etc.
  • 6-membered, nitrogen-containing heterocyclic rings having one or two nitrogen atoms in addition to carbon atoms e.g., pyridine and pyrazine rings, etc.
  • 5-membered aromatic heterocyclic rings having one sulfur atom in addition to carbon atoms e.g., thiophene ring, etc.
  • non-aromatic heterocyclic ring includes, for example, 5-membered to 9-membered, non-aromatic heterocyclic rings, preferably 5-membered or 6-membered, non-aromatic heterocyclic rings, having from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms , etc .
  • Ring A includes tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole , dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydroxazole and dihydroisoxazole rings, etc.; and Ring B includes , in addition to the above mentioned rings , piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene , tetrahydrof ran, tetrahydrothiazole, tetrahydroisothiazole, t
  • Ring A includes, for example, 6-membered, non-aromatic heterocyclic rings having one or two nitrogen atoms in addition to carbon atoms (e.g., tetrahydropyridine, tetrahydropyrimidine and tetrahydropyridazine rings , etc. ) , etc., and is especially preferably a tetrahydropyridine ring, etc.
  • Ring B includes, for example, 6- membered, non-aromatic heterocyclic rings having one or 2 nitrogen atoms in addition to carbon atoms (e.g. , piperidine and piperazine rings, etc.), etc., and is especially preferably a piperazine ring, etc.
  • the "cyclic hydrocarbon ring (homocyclic ring)" includes, for example, 3-membered to 10-membered (for example, 5-membered to 9-membered) cyclic hydrocarbon rings , preferably 5-membered or 6-membered cyclic hydrocarbon rings, etc.
  • Ring A includes benzene, C 3 . 10 cycloalkenes (e.g. , cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), etc.
  • the cycloalkenes are preferably C 5 .
  • Ring B includes, in addition to the above mentioned rings, C 3 . 10 cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.), etc.
  • the cycloalkanes are preferably C 5-6 cycloalkanes (e.g., cyclohexane, cyclopentane, etc.), etc.
  • Ring A includes , for example, 6-membered homocyclic rings such as benzene and cyclohexene rings , etc .
  • Ring B preferably includes, for example, 6-membered homocyclic rings such as benzene and cyclohexane rings , etc .
  • a benzene ring is especially preferred.
  • Ring A and Ring B is an optionally- substituted heterocyclic ring. Both of Ring A and Ring B may be optionally substituted heterocyclic rings.
  • one of Ring A and Ring B is 1) an optionally substituted aromatic ring and the other is 2) an optionally substituted aromatic heterocyclic ring (preferably, aromatic heterocyclic ring) .
  • aromatic ring includes, for example, (i) the above-mentioned “aromatic heterocyclic rings", namely, optionally substituted, 5-membered or 6-membered, aromatic heterocyclic rings having the same one or different two hetero atoms selected from nitrogen, sulfur and oxygen atoms , preferably from 1 to 3 such hetero atoms , in addition to carbon atoms (e.g., pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings, etc.), or (ii) optionally substituted benzene rings.
  • aromatic heterocyclic rings having the same one or different two hetero atoms selected from nitrogen, sulfur and oxygen atoms , preferably from 1 to 3 such hetero atoms , in addition to carbon atoms (e.g., pyridine, pyr
  • aromatic heterocyclic ring of the above-mentioned 2) "optionally substituted aromatic heterocyclic ring” includes, for example, the same aromatic heterocyclic rings as those in the above-mentioned "5-membered or 6-membered, aromatic heterocyclic ring” .
  • aromatic heterocyclic ring for example, referred to are the same substituents as those for Ring A and Ring B which are mentioned hereinunder.
  • the "5-membered or 6-membered, aromatic heterocyclic ring” preferably includes the same heterocyclic rings as those referred to hereinabove for the foregoing "aromatic heterocyclic ring” .
  • one of Ring A and Ring B is an optionally substituted aromatic heterocyclic ring (e.g. , a 5-membered or 6-membered aromatic heterocyclic ring) and the other is an optionally substituted benzene ring.
  • aromatic heterocyclic ring e.g. , a 5-membered or 6-membered aromatic heterocyclic ring
  • the substituents for the optionally substituted "homocyclic or heterocyclic ring”, “aromatic heterocyclic ring”, “non-aromatic heterocyclic ring”, “cyclic hydrocarbon ring” , “aromatic ring” and “benzene ring” to be represented by Ring A and Ring B include, for example, a halogen atom, an optionally substituted alkyl group, an optionally halogenated alkoxy group, an optionally halogenated alkylthio group, an aryl group, an acylamino group, an acyloxy group, a hydroxy group, a nitro group, a cyano group, an amino group, a mono- or di-alkylamino group, a cyclic amino group (e.g.
  • a cyclic amino group optionally having hetero atom selected from oxygen atom, sulfur atom, etc. , in addition to nitrogen atom) , an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxycarbonyl group , a carboxyl group, an alkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsulfonyl group, an oxo group, etc.
  • halogen atom which Ring A and Ring B may have, includes, for example, fluorine, chlorine, bromine and iodine atoms.
  • the halogen atom includes, for example, fluorine, chlorine and bromine atoms (especially, fluorine and chlorine atoms, etc.).
  • halogen atom e.g. , fluorine, chlorine and bromine atoms, etc.
  • halogen atom e.g. , fluorine, chlorine and bromine atoms, etc.
  • optionally-halogenated alkyl groups for example, C ⁇ alkyl groups, and C ⁇ alkyl groups substituted by 1 to 4 halogen atoms, etc.
  • alkyl groups and halogenated alkyl groups include, for example, methyl, chloromethyl, fluoromethyl , difluoromethyl , trichloromethyl , trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3, 3,3-trifluoropropyl, isopropyl, 1- (trifluoromethyl)ethyl, butyl, 4,4,4- trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, 4- trifluoromethylbutyl, hexyl, 6,6,6-trifluorohexy1 and 5-trifluoromethylpentyl groups, etc.
  • the "optionally substituted alkyl group” includes optionally halogenated C x _ 4 alkyl groups, for example, C 1-4 alkyl groups and C ⁇ alkyl groups substituted by 1 to 3 halogen atoms, etc.
  • the "optionally halogenated alkoxy group", which Ring A and Ring B may have , includes , for example , alkoxy groups or alkoxy groups substituted by 1 to 5 halogen atoms such as those mentioned hereinabove , etc .
  • alkoxy groups or halogenated alkoxy groups include, for example, methoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2, 2 , 2-trifluoroethoxy, 2,2,2- trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4, 4, 4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy and hexyloxy groups, etc.
  • the "optionally halogenated alkoxy group” includes C ⁇ alkoxy groups or C x _ 4 alkoxy group substituted by 1 to 3 halogen atoms , for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2 ,2 ,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4 , 4-trifluorobutoxy, isobutoxy and sec-butoxy groups, etc.
  • the "optionally halogenated alkylthio group", which Ring A and Ring B may have, includes, for example, alkylthio groups, and alkylthio groups having 1 to 5 halogen atoms such as those mentioned hereinabove, etc.
  • alkylthio groups and halogenated alkylthio groups include, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4 ,4 ,4-trifluorobutylthio, pentylthio and hexylthio groups, etc.
  • the "optionally halogenated alkylthio group” includes C 1 _ 4 alkylthio groups, or C ⁇ _ 4 alkylthio groups substituted by 1 to 3 halogen atoms , for example, methylthio, difluoromethylthio , trifluoromethylthio, ethylthio, propylthio, isopropylthio. butylthio and 4, 4, 4-trifluorobutylthio groups, etc.
  • the aryl group as the substituent includes C 6 . 10 aryl groups (e.g., phenyl group, etc.); the acylamino group includes, for example, C ⁇ acylamino groups (e.g., formylamino , acetylamino , propionylamino , butyrylamino and benzoylamino groups, etc.), etc.
  • the acyloxy group includes, for example, C 1 . 3 acyloxy groups (e.g., formyloxy, acetoxy and propionyloxy groups, etc.), etc.
  • the mono- or di-alkylamino group includes, for example, mono- or di- C ⁇ _ 4 alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino and diethylamino groups, etc. ) , etc.
  • the cyclic amino group includes, for example, 5- membered to 9-membered cyclic amino groups optionally having from 1 to 3 hetero atoms, such as oxygen atom, sulfur atom, etc. , in addition to nitrogen atom (e.g. , pyrrolidino, piperidino and morpholino groups , etc . ) , etc .
  • the alkylcarbonylamino group includes, for example, C x . 4 alkyl-carbonylamino groups (e.g., acetylamino, propionylamino and butyrylamino groups , etc . ) ; the alkylsulfonylamino group includes, for example, C ⁇ alkylsulfonylamino groups (e.g., methylsulfonylamino and ethylsulfonylamino groups, etc.
  • the alkoxycarbonyl group includes, for example, C ⁇ alkoxy-carbonyl groups (e.g., methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl and butoxycarbonyl groups, etc.);
  • the alkylcarbonyl group includes, for example, alkylcarbonyl groups (e.g., formyl, methylcarbonyl, ethylcarbonyl and propylcarbonyl groups, etc.);
  • the mono- or di-alkylcarbamoyl group includes, for example, mono- or di-C ⁇ ,, alkylcarbamoyl groups (e.g., methylcarbamoyl , ethylcarbamoyl , dimethylcarbamoyl and diethylcarbamoyl groups, etc.
  • alkylsulfonyl group includes, for example, C x . 6 alkylsulfonyl groups (e.g., methylsulfonyl, ethylsulfonyl and propylsulfonyl groups, etc. ) , etc.
  • alkylsulfonyl groups e.g., methylsulfonyl, ethylsulfonyl and propylsulfonyl groups, etc.
  • halogen atoms if substituted, is from 1 to 5, preferably from 1 to 3.
  • Ring A and Ring B include a halogen atom, an optionally halogenated C x _ 4 alkyl group, an optionally halogenated C ⁇ alkoxy group, an optionally halogenated C ⁇ alkylthio group, a C ⁇ - j acyloxy group, a hydroxy group, an amino group, a mono- or di-Ci. 4 alkylamino group, a carboxyl group, a C ⁇ , 4 alkoxy-carbonyl group, an oxo group, etc.
  • More preferred substituents for the optionally substituted Ring A and Ring B include a halogen atom, an optionally halogenated C ⁇ alkyl group, an optionally halogenated C ⁇ alkoxy group, a hydroxy group, an amino group, a mono- or di-C ⁇ alkylamino group, a C 1 _ 3 acyloxy group, an oxo group, etc.
  • the substituents for Ring A and Ring B may be at any substitutable position. If the rings are substituted by two or more substituents, the substituents may be the same or different. The number of the substituents may be from 1 to 4 , preferably from 1 to 3.
  • the ring may form a quaternary salt .
  • it may form a salt with halide ion(s) (e.g., Cl “ , Br “ , I “ , etc.) or other anion(s) such as sulfato ion, hydroxy ion, etc.
  • Preferred homocyclic rings for Ring A are optionally substituted homocyclic rings composed of carbon atoms, for example, including those of a formula (A-l):
  • an optionally-halogenated C x . 4 alkyl group e.g., methyl, isopropyl, trifluoromethyl , trichloromethyl , ethyl, 2, 2, 2-trifluoroethyl and pentafluoroethyl groups, etc.
  • an optionally halogenated C x . 4 alkoxy group e.g. , methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2- trifluoroethoxy and pentafluoroethoxy groups, etc.
  • A-2 a formula (A-2):
  • a 2 and A 3 are the same or different and represent, independently, a halogen atom (e.g. , fluorine and chlorine atoms, etc.), an optionally halogenated C ⁇ ,, alkyl group (e.g., methyl, isopropyl, trifluoromethyl , trichloromethyl, ethyl, 2, 2, 2-trifluoroethyl and pentafluoroethyl groups, etc. ) , or an optionally halogenated C ⁇ alkoxy group (e.g. , methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2, 2-trifluroroethoxy and pentafluoroethoxy groups, etc. ) .
  • a halogen atom e.g. , fluorine and chlorine atoms, etc.
  • an optionally halogenated C ⁇ , alkyl group e.g., methyl, isopropyl, tri
  • More preferred homocyclic rings include, for example, benzene rings of a formula (A-3):
  • a 4 and A 5 are the same or different and represent , independently, a halogen atom (e.g., fluorine and chlorine atoms, etc. ) , or an optionally-halogenated C ⁇ alkyl group (e.g., methyl, trifluoromethyl , trichloromethyl, ethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl and isopropyl groups , etc. ) .
  • a halogen atom e.g., fluorine and chlorine atoms, etc.
  • an optionally-halogenated C ⁇ alkyl group e.g., methyl, trifluoromethyl , trichloromethyl, ethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl and isopropyl groups , etc.
  • a 1 is a halogen atom (e.g. , fluorine and chlorine atoms, etc.), or an optionally- substituted C ⁇ alkyl group (e.g. , methyl, trifluoromethyl, ethyl and isopropyl groups, etc.).
  • halogen atom e.g. , fluorine and chlorine atoms, etc.
  • C ⁇ alkyl group e.g. , methyl, trifluoromethyl, ethyl and isopropyl groups, etc.
  • a 2 and A 3 are the same or different and represent, independently, an optionally- halogenated C 1 _ i alkyl group (e.g. , methyl, trifluoromethyl , ethyl and isopropyl groups, etc.), or an optionally- halogenated C ⁇ alkoxy group (e.g., methoxy, trifluoromethoxy and ethoxy groups , etc . ) .
  • C 1 _ i alkyl group e.g. , methyl, trifluoromethyl , ethyl and isopropyl groups, etc.
  • C ⁇ alkoxy group e.g., methoxy, trifluoromethoxy and ethoxy groups , etc .
  • Homocyclic rings where A 4 and A 5 are the same or different and represent, independently, a C ⁇ alkyl group (e.g., methyl, ethyl and isopropyl groups, etc.).
  • a 1 is a halogen atom (e.g., fluorine and chlorine atoms , etc . ) .
  • Preferred aromatic heterocyclic or non-aromatic heterocyclic rings for Ring A are 5-membered or 6-membered, aromatic heterocyclic or non-aromatic heterocyclic rings including, for example, pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole and thiazole rings, etc. Concretely, for example, preferred are heterocyclic rings of a formula (A-5):
  • optionally substituted aromatic or non-aromatic heterocyclic rings for Ring A are pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole and thiazole rings, etc. optionally having one or two substituents selected from an oxo group, an optionally substituted alkyl group (this has the same meaning as the substituent for the optionally substituted Ring A and Ring B) , a C 6 . 10 aryl group (e.g., phenyl group, etc.) and a halogen atom (e.g., fluorine, chlorine and bromine atoms , etc . ) .
  • D 1 represents a hydrogen atom, a halogen atom (e.g. , fluorine, chlorine and bromine atoms, etc.); E 1 represents a C x _ 4 alkyl group (e.g. , methyl, ethyl, propyl and isopropyl groups, etc.); the compounds having the partial structure of (ii) form quaternary ammonium salts along with a halide ion (e.g., Cl ⁇ , Br " , I " , etc.), a sulfato ion, a hydroxy ion X
  • G represents a hydrogen atom or a C x . 4 alkyl group (e.g., methyl, ethyl, propyl and isopropyl groups, etc.); J represents a hydrogen atom, a C x _ 4 alkyl group (e.g., methyl, ethyl , propyl and isopropyl groups , etc . ) or a C 6 . 10 aryl group (e.g., phenyl group , etc. ) .
  • Ring A is preferably a 5-membered or a 6-membered, nitrogen-containing heterocyclic ring, for example, (i) a 6-membered, aromatic, nitrogen-containing heterocyclic ring having one or two nitrogen atoms in addition to carbon atoms (e.g., pyridine and pyrazine rings, etc.), (ii) a 6-membered, non-aromatic heterocyclic ring having one or two nitrogen atoms in addition to carbon atoms (e.g., tetrahydropyridine , tetrahydropyrimidine and tetrahydropyridazine rings , etc.), or the like.
  • Ring A is an aromatic, nitroge -containing heterocyclic ring, particularly, a pyridine ring or the like.
  • ring A is a pyridine ring which may be substituted by 1 to 3 substituents selected from a halogen atom or C 1 . 4 alkyl group.
  • Preferred homocyclic rings for Ring B are optionally substituted homocyclic rings consisting of carbon atoms, for example, including those of a formula (B-l):
  • B 1 represents a halogen atom, a C x . 4 alkyl group optionally substituted by hydroxy or optionally halogenated , an optionally halogenated C ⁇ _ ⁇ alkoxy group, a alkylcarbonyl group or a carboxyl group; those of a formula (B-2):
  • B 2 and B 3 are the same or different and represent , independently, a halogen atom, an optionally halogenated C 1-4 alkyl group or an optionally halogenated C 1 _ i alkoxy group; and those of a formula (B-3):
  • B 4 , B 5 and B 6 are the same or different and represent , independently, a halogen atom, an optionally halogenated C x _ t alkyl group or an optionally halogenated C ⁇ _ 4 alkoxy group . More preferred are homocyclic rings of a formula (B-4) :
  • B 7 , B 8 and B 9 are the same or different and represent, independently, a halogen atom, an optionally halogenated C X _ alkyl group or an optionally halogenated C ⁇ ,, alkoxy group.
  • B 10 represents, a halogen atom, a C ⁇ _ alkyl group optionally substituted by hydroxy or optionally halogenated , an optionally halogenated C 1 _ i alkoxy group, a alkylcarbonyl group or a carboxyl group.
  • the halogen atom for any of B 1 to B 10 includes, for example, fluorine, chlorine and bromine atoms, etc.
  • the optionally-halogenated C 1 _ i alkyl group includes , for example , methyl , trifluoromethyl , trichloromethyl, ethyl, 2 , 2, 2-trifluoroethyl, 2,2,2- trichloroethyl , 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, propyl, 2 , 2, 3 , 3-tetrafluoropropyl and isopropyl groups, etc.
  • the optionally-halogenated C 1 _ i alkoxy group includes, for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2- trifluoroethoxy, 2, 2 , 2-trichloroethoxy, 1,1,2,2-2-
  • Ring B is also preferably an optionally substituted benzene ring, which includes, for example, benzene rings of a formula (B-6):
  • B 1 , B 2 , B 3 , B 4 , B 5 and B 6 are the same or different and represent, independently, a halogen atom (e.g.. X
  • C 2 . 4 alkyl group e.g. , methyl, trifluoromethyl, ethyl and isopropyl groups, etc.
  • B 1 , B 2 , B 3 , B 4 , B 5 and B 6 are the same or different and represent , independently, an optionally-halogenated C ⁇ alkoxy group (e.g., methoxy, trifluoromethoxy and ethoxy groups, etc. ) .
  • B 7 , B 8 and B 9 represent halogen atoms (e.g. , fluorine and chlorine atoms, etc.).
  • B 10 represents a fluorine atom.
  • B 10 represents a C ⁇ alkyl group (e.g. , methyl group, etc. ) .
  • Bl or BIO represents a alkyl group which may be substituted by hydroxy (e,g, hydroxymethyl , etc. ) , a alkylcarbonyl group (e.g., formyl, acetyl, etc.), a carboxyl group.
  • More preferred optionally substituted benzene rings are phenyl groups of a formula (B-9):
  • aromatic heterocyclic rings or non-aromatic heterocyclic rings for Ring B are 5-membered or 6-membered aromatic heterocyclic rings or non-aromatic heterocyclic rings such as pyridine, thiophene and piperidine rings, etc. These rings may optionally be substituted by substituents such as those mentioned hereinabove as preferred substituents for Ring A.
  • Ring B is an aromatic heterocyclic ring or a non-aromatic heterocyclic ring, it especially preferably includes, for example, heterocyclic rings of a formula (B-10) :
  • Ring A and Ring B is/are heterocyclic ring(s)
  • the ring(s) is/are also preferably unsubstituted one(s) .
  • Preferred combinations of Ring A and Ring B ( 1 ) are as follows :
  • Ring A and Ring B is a 5-membered or 6-membered heterocyclic ring having one or two hetero atoms selected from nitrogen and sulfur atoms in addition to carbon atoms (e.g., pyridine, pyrazine, thiophene, tetrahydropyridine, piperidine and piperazine rings, etc.) which may be optionally substituted by C ⁇ alkyl group(s) (e.g. , methyl, ethyl and isopropyl groups, etc.).
  • C ⁇ alkyl group(s) e.g. , methyl, ethyl and isopropyl groups, etc.
  • Ring A and Ring B is a benzene ring optionally substituted by from 1 to 3 substituents selected from a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.), an optionally halogenated C 1 . 4 alkyl group (e.g., methyl, trifluoromethyl, trichloromethyl, ethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl, 2,2,2- trichloroethyl, propyl and isopropyl groups, etc.) and an optionally halogenated C x .
  • a halogen atom e.g., fluorine, chlorine and bromine atoms, etc.
  • an optionally halogenated C 1 . 4 alkyl group e.g., methyl, trifluoromethyl, trichloromethyl, ethyl, 2, 2, 2-trifluoroethyl, pentaflu
  • Ring A and Ring B (2) are as follows :
  • Ring A and Ring B is a 5-membered or 6-membered aromatic heterocyclic ring having one or two hetero atoms selected from nitrogen and sulf r atoms in addition to carbon atoms (e.g., pyridine, pyrazine and thiophene rings, etc. ) .
  • Ring A and Ring B is a benzene ring optionally substituted by from 1 to 3 substituents selected from a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.), an optionally halogenated C ⁇ alkyl group (e.g., methyl, trifluoromethyl, trichloromethyl, ethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl, 2,2,2- trichloroethyl, propyl and isopropyl groups, etc.) and an optionally halogenated C ⁇ alkoxy group (e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2- trifluoroethoxy, pentafluoroethoxy, 2 , 2, 2-trichloroethoxy, propoxy and isopropoxy groups, etc.).
  • a halogen atom e.g., fluor
  • Ring A is an optionally substituted aromatic heterocyclic ring such as mentioned above (e.g., an optionally substituted, 5-membered or 6-membered aromatic heterocyclic ring, especially pyridine ring, etc.), while Ring B is an optionally substituted benzene ring.
  • aromatic heterocyclic ring such as mentioned above (e.g., an optionally substituted, 5-membered or 6-membered aromatic heterocyclic ring, especially pyridine ring, etc.)
  • Ring B is an optionally substituted benzene ring.
  • Ring C represents an optionally substituted homocyclic ring or an optionally substituted heterocyclic ring.
  • the homocyclic ring or the heterocyclic ring may have 1 to 5 , preferably 1 to 3 substituents, which may be the same or different.
  • the substituents may be positioned at any position of the homocyclic or heterocyclic ring.
  • the homocyclic ring includes "cyclic hydrocarbon (homocyclic) rings" such as those as referred to hereinabove for “Ring A and Ring B” , for example, from 3-membered to 10-membered cyclic hydrocarbon rings such as benzene, C 3 . 10 cycloalkenes (e.g. , cyclobutene, cyclopentene, cyclohexene, cycloheptene , cyclooctene, etc.), C 3 .
  • cyclic hydrocarbon (homocyclic) rings such as those as referred to hereinabove for "Ring A and Ring B” , for example, from 3-membered to 10-membered cyclic hydrocarbon rings such as benzene, C 3 . 10 cycloalkenes (e.g. , cyclobutene, cyclopentene, cyclohexene, cycloheptene , cyclooctene, etc.),
  • cycloalkanes e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.
  • cycloalkanes e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.
  • 5-membered or 6- membered cyclic hydrocarbon rings preferably 5-membered or 6- membered cyclic hydrocarbon rings.
  • 6-membered homocyclic rings such as benzene, cyclohexene and cyclohexane rings, etc.
  • benzene ring Especially preferred is benzene ring.
  • the substituents for the homocyclic rings such as the above-mentioned benzene ring include, for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine atoms), an optionally-halogenated C ⁇ alkyl group (e.g., methyl, chloromethyl, difluoromethyl trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2- trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3, 3, 3-trifluoropropyl, butyl, isobutyl, t-butyl, perfluorobutyl, pentyl, hexyl, octyl and decyl groups, etc.), an amino-substituted C 1 _ i alkyl group (e.g., aminomethyl and 2-aminoethyl groups, etc.),
  • alkylamino-substituted C ⁇ alkyl group e.g., methylaminomethyl , dimethylaminomethyl, 2-aminoethyl and 2-dimethylaminoethyl groups, etc.
  • carboxyl-substituted C- L . 4 alkyl group e.g. , carboxymethyl and carboxyethyl groups , etc.
  • a C 1 _ i alkoxy-carbonyl-substituted C ⁇ alkyl group e.g. , methoxycarbonylethyl and ethoxycarbonylethyl groups , etc.
  • a hydroxy-substituted C x e.g., hydroxy-substituted C x .
  • alkyl group e.g., hydroxymethyl and hydroxyethyl groups, etc.
  • C x e.g., hydroxymethyl and hydroxyethyl groups, etc.
  • alkoxy-carbonyl-substituted C ⁇ alkyl group e.g., methoxymethyl, ethoxyethyl and ethoxyethyl groups, etc.
  • C 3 a C 3 .
  • cycloalkyl group e.g., cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl , cycloheptyl and cyclooctyl groups , etc.
  • a nitro group e.g., a cyano group, a hydroxy group
  • an optionally-halogenated C ⁇ alkoxy group e.g., methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2, 2 ,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy, octyloxy and decyloxy groups, etc.), an optionally-halogenated C ⁇ alkylthio group (e.g., methylthio, difluoromethyl
  • a cyclic amino group e.g. , a 5-membered to 9-membered cyclic amino group optionally having from 1 to 3 hetero atoms such as oxygen and sulfur atoms, etc., in addition to nitrogen atoms, concretely for example, pyrrolidino, piperidino and morpholino groups, etc.
  • aC w alkyl-carbonylamino group e.g., acetylamino, propionylamino and butyrylamino groups , etc .
  • an aminocarbonyloxy group a mono- or di-C ⁇ , alkylaminocarbonyloxy group (e.g. , methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy and diethylaminocarbonyloxy groups , etc .
  • alkylaminocarbonyloxy group e.g. , methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy and diethylaminocarbonyloxy groups , etc .
  • a C ⁇ alkylsulfonylamino group e.g., methylsulfonylamino, ethylsulfonylamino and propylsulfonylamino groups, etc.
  • a C x _ 4 alkoxy-carbonyl group e.g., methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl , butoxycarbonyl and isobutoxycarbonyl groups, etc.
  • an aralkyloxycarbonyl group e.g., benzyloxycarbonyl group, etc.
  • a carboxyl group e.g., methylcarbonyl, ethylcarbonyl and butylcarbonyl groups , etc .
  • a C 3 . 6 cycloalkyl-carbonyl group e.g. , cyclohexylcarbonyl group, etc.
  • a carbamoyl group a mono- or di-C ⁇ ,
  • alkylcarbamoyl group e.g., methylcarbamoyl , ethylcarbamoyl , propylcarbamoyl, butylcarbamoyl , diethylcarbamoyl and dibutylcarbamoyl groups, etc.
  • a C _ 6 alkylsulfonyl group e.g., methylsulfonyl , ethylsulfonyl and propylsulfonyl groups, etc.
  • the homocyclic Ring C may optionally be substituted, for example, by one 5-membered or 6-membered, aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 , 2 ,3-oxadiazolyl, 1 , 2, 4-oxadiazolyl, 1,3,4- oxadiazolyl, furazanyl, 1 , 2 , 3-thiadiazolyl, 1,2,4- thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2 , 3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl groups, etc.), etc., and the aromatic monocyclic heterocyclic group may optionally be substituted
  • halogen atom e.g., fluorine, chlorine and bromine atoms, etc.
  • an optionally halogenated alkyl group e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2- trifluoroethyl, perfluoroethyl , propyl, isopropyl, 3, 3, 3-trifluoropropyl, butyl, s-butyl, t-butyl and perfluorobutyl groups , etc .
  • a nitro group a hydroxy group, an optionally halogenated alkoxy group (e.g. , methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2- trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy,
  • an optionally halogenated alkoxy group e.g. , methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2- trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy
  • an amino group e.g., methylaminomethyl , dimethylaminomethyl, 2- methylaminoethyl and 2-dimethylaminoethyl groups, etc.
  • a mono- or di-C ⁇ , alklamino group e.g., methylamino, ethylamino , dimethylamino and diethylamino groups , etc .
  • a C ] ⁇ alkoxy-carbonyl group e.g., methoxycarbonyl and ethoxycarbonyl groups, etc.
  • a carboxyl group e.g., methoxycarbonyl and ethoxycarbonyl groups, etc.
  • a halogen atom e.g., fluorine, chlorine and bromine atoms, etc.
  • an optionally halogenated C ⁇ ,, alkyl group e.g.
  • methyl chloromethyl , difluoromethyl, trichloromethyl, trifluoromethyl , ethyl, 2-bromoethyl, 2,2, 2-trichloroethyl, 2 , 2, 2-trifluoroethyl, perfluoroethyl, propyl, isopropyl and t-butyl groups, etc.
  • an optionally halogenated C x _ 4 alkoxy group e.g. , methoxy, trifluoromethoxy, ethoxy, 2, 2, 2-trichloroethoxy, 2,2,2- trifluoroethoxy, perfluoroethoxy and propoxy groups , etc.
  • the number of the substituents is, for example, from 1 to 3.
  • halogen atom e.g., fluorine, chlorine and bromine atoms, etc.
  • an optionally halogenated C ⁇ alkyl group e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2, 2, 2-trichloroethyl, 2 , 2 , 2-trifluoroethyl, perfluoroethyl , propyl, isopropyl and t-butyl groups, etc.
  • an optionally halogenated C- ⁇ alkoxy group e.g. , methoxy, trifluoromethoxy, ethoxy, 2 , 2, 2-trichloroethoxy, 2,2,2- trifluoroethoxy, perfluoroethoxy and propoxy groups , etc.
  • heterocyclic ring of the “optionally substituted heterocyclic ring” includes, for example, from 5-membered to 10-membered heterocyclic rings having 1 to 4 hetero atoms of the same type or different two types, such as nitrogen, oxygen, sulfur atoms, etc., in addition to carbon atoms, etc.
  • the heterocyclic ring includes, for example;
  • 5-membered or 6-membered, aromatic monocyclic heterocyclic rings such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 ,2 ,3-oxadiazolyl, 1, 2 , 4-oxadiazolyl, 1,3,4- oxadiazolyl, furazanyl, 1, 2, 3-thiadiazolyl, 1,2,4- thiadiazolyl, 1 , 3, 4-thiadiazolyl, 1, 2 ,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.;
  • phenazinyl phenoxathinyl , thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[ 1 , 2-b]pyridazinyl, pyrazolo[l.5-a]pyridyl, imidazo[ 1 , 2-b]pyridazinyl, imidazo [ 1 , 2-a]pyrimidinyl, 1,2,4-triazolo [ 4 , 3-a]pyridyl , 1, 2,4-triazolo[ 4 , 3-b]pyridazinyl, etc.;
  • heterocyclic rings (1) to (3) for example, 5-membered or 6-membered heterocyclic rings having from 1 to 3 hetero atoms, such as nitrogen, oxygen and sulfur atoms, etc., in addition to carbon atoms, are widely utilized.
  • Such heterocyclic rings include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl, thiadiazolyl, thiophenyl, etc.
  • substituents for the optionally substituted heterocyclic rings mentioned are substituents such as those as referred to hereinabove for the foregoing "optionally substituted homocyclic rings".
  • Ring C includes optionally substituted benzene rings (especially, substituted benzene rings) , for example, benzene rings optionally substituted by 1 to 3 substituents selected from a halogen atom, an optionally halogenated C ⁇ alkyl group, an optionally substituted C ⁇ alkoxy group, a acyloxy group and a hydroxy group (especially, benzene rings substituted by such substituent ( s ) ) .
  • the preferred Ring C includes, for example, optionally substituted benzene rings of a formula (C-l):
  • C 1 , C 2 and C 3 are the same or different and represent, independently, a hydrogen atom, a halogen atom, an optionally halogenated C 1 . i alkyl group, an optionally halogenated C x _ 4 alkoxy group, a mono- or di-C 1 . 4 alkylamino group, a C ⁇ acyloxy group or a hydroxy group; and optionally substituted benzene rings of a formula (C-2):
  • C 4 and C 5 are the same or different and represent , independently, a hydrogen atom, a halogen atom, an optionally halogenated C ⁇ alkyl group or an optionally halogenated C ⁇ alkoxy group.
  • the halogen atom, the optionally halogenated C ⁇ alkyl group, the optionally halogenated C ⁇ alkoxy group and the mono- or di-C 1 . 4 alkylamino group to be represented by any of C 1 , C 2 , C 3 , C 4 and C 5 may be the same as the above-mentioned halogen atom, optionally halogenated C ⁇ ,, alkyl group, optionally halogenated C ⁇ alkoxy group and mono- or di- C 1 . i alkylamino group, respectively.
  • Ring C includes, for example, benzene rings of the above-mentioned formulae (C-1) and (C-2) where C 1 to C 5 are as follows:
  • C 1 , C 2 and C 3 are the same or different and represent, independently, a halogen atom, an optionally halogenated C ⁇ _ 4 alkyl group or an optionally halogenated C x . 4 alkoxy group;
  • C 1 , C 2 and C 3 are the same or different and represent, independently, a halogen atom or an optionally halogenated C ⁇ alkyl group;
  • C 1 , C 2 and C 3 are the same or different and represent, independently, a halogen atom
  • C 1 , C 2 and C 3 are the same or different and represent, independently, an optionally halogenated C ⁇ alkyl group
  • C 1 , C 2 and C 3 are the same or different and represent, independently, an optionally halogenated C 1 . 4 alkoxy group;
  • C 4 and C 5 are the same or different and represent, independently, a halogen atom
  • ( 7 ) C 4 and C 5 are the same or different and represent , independently, an optionally halogenated C ⁇ alkyl group; or
  • ( 8 ) C 4 and C 5 are the same or different and represent , independently, an optionally halogenated C ⁇ alkoxy group.
  • Ring C includes, for example, benzene rings of the above-mentioned formula (C-2) where C 4 and C 5 are as follows:
  • one of C 4 and C 5 is a methoxy group and the other is a 1-methoxy-1-methylethyl group;
  • Ring Z represents an optionally-substituted nitrogen containing heterocyclic ring.
  • substituents are referred to as substituents for Ring Z , which include , for example , an alkyl group (e.g. , a linear or branched alkyl group having from 1 to 6 carbon atoms, preferably a linear or branched alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups , etc . ) , an alkenyl group (e.g., an alkenyl group having from
  • 2 to 4 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl sec-butenyl groups, etc.
  • an alkynyl group e.g., an alkynyl group having from 2 to 6 carbon atoms , preferably an alkynyl group having from 2 to 4 carbon atoms , such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl and sec-butynyl groups, etc.
  • a cycloalkyl group e.g., a C 3 . 8 cycloalkyl group, preferably a C 3 .
  • cycloalkyl group such as cyclopropyl , cyclobutyl, cyclopentyl and cyclohexyl groups, etc.
  • a cycloalkyl-alkyl group e.g., a C 3 . 6 cycloalkyl-C ⁇ alkyl group, such as cyclopropylmethyl, cyclopropylethyl and cyclohexylmethyl groups , etc .
  • an aryl group e.g., an aryl group having from 6 to 14 carbon atoms, preferably an aryl group having from 6 to 10 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, anthryl and phenanthryl groups, etc., especially, phenyl group
  • a nitro group e.g., a cyano group, a hydroxy group, a C ⁇ ,, alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy and butoxy groups, etc.)
  • a C 1-4 alkylthio group e.g., methylthio, ethylthio and propylthio groups , etc .
  • an amino group a mono- or di-C ⁇ , a alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino and diethylamino groups, etc.), a cyclic amino group (e.g., a 5-membered to 9-membered cyclic amino group optionally having from 1 to 3 hetero atoms , such as oxygen and sulfur atoms, etc., in addition to nitrogen atom, concretely, for example, pyrrolidino, piperidino, morpholino and thiomorpholino groups, etc.), a C x . 4 alkyl-carbonylamino group (e.g.
  • acetylamino e.g., acetylamino , propionylamino and butyrylamino groups, etc.
  • a C ⁇ , alkylsulfonylamino group e.g., methylsulfonylamino and ethylsulfonylamino groups , etc .
  • a ⁇ _ 4 alkoxy-carbonyl group e.g., methoxycarbonyl , ethoxycarbonyl and propoxycarbonyl groups, etc.
  • a carboxyl group e.g., methoxycarbonyl , ethoxycarbonyl and propoxycarbonyl groups, etc.
  • a carboxyl group e.g., methoxycarbonyl , ethoxycarbonyl and propoxycarbonyl groups, etc.
  • a carboxyl group e.g., methoxycarbonyl , ethoxycarbonyl and propoxycarbonyl groups, etc.
  • a carboxyl group e.g., a C ⁇ alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl and propylcarbonyl groups , etc.)
  • a carbamoyl group a mono- or di-C ⁇
  • alkylcarbamoyl group
  • the number of the substituents is , for example , from 1 to 5 , preferably 1 or 2 , depending on the size of Ring Z.
  • Ring Z may be a heterocyclic ring optionally having at least one hetero atom selected from nitrogen, oxygen and sulfur atoms, in addition to Y and the nitrogen atom N, and is preferably an optionally oxoated ring.
  • Ring Z includes rings of a formula (Z-l):
  • D and E represent groups from which Ring Z as mentioned above is formed together with the nitrogen atom adjacent to E.
  • D and E which form Ring Z represent, independently, an alkylene group optionally having an oxo group, oxyalkylene group, or iminoalkylene group.
  • the alkylene groups optionally having an oxo group to be represented by D and E preferably have carbon atoms from which Ring Z is formed to be a 5-membered to 12-membered ring, preferably a 5-membered to 9-membered ring.
  • the numbers of the carbon atoms that constitute the alkylene groups of D and E may be the same or different.
  • D includes, for example, C x . 7 alkylene group optionally having an oxo group, especially C ⁇ alkylene group optionally having an oxo group C ⁇ oxyalkylene groups , especially C ⁇ _ 5 oxyalkylene groups , C ⁇ , iminoalkylene groups , especially C 1-5 imminoalkylene groups.
  • D includes an alkylene group of a formula -(CH 2 ) m - (where m is from 1 to 7) , an oxyalkylene group of a formula -0-(CH 2 )p (where p is from 1 to 7), iminoalkylene group of a formula -NH-(CH 2 )q (where q is from 1 to 7.
  • m is preferably from 1 to 5, more preferably from 2 to 5.
  • E includes, for example, C ⁇ alkylene group optionally having an oxo group, more preferably an alkylene X
  • the number of the oxo groups that are substitutable in Ring Z is not specifically limited but may be selected from 1 to 3 depending on the size of Ring Z . Where Ring Z is a 5-membered to 10-membered ring, the number of the substitutable oxo groups is 1 or 2.
  • Oxo group(s) may be substituted at at least either one of D and/or E . Preferably, oxo group(s) is/are substituted at E in Ring Z.
  • Ring Z includes, for example, from 5-membered to 9-membered rings of a formula (Z-2):
  • each m and p independently, represents an integer of from 1 to 5.
  • n represents an integer of from 1 to 6 , preferably an integer of from 1 to
  • Ring A and Ring B is a 5-membered or 6-membered heterocyclic ring having one or two hetero atoms selected from nitrogen and oxygen atoms , in addition to carbon atoms , while the other is a benzene ring, and the Rings A and B may optionally have one or two substituents selected from a halogen atom and an optionally halogenated C ⁇ ,, alkyl group; Ring C is a benzene ring optionally having from 1 to 3 substituents selected from a halogen atom, an optionally halogenated alkyl group) and an optionally halogenated C ⁇ alkoxy group (preferably, Ci.
  • D that constitutes Ring Z is -(CH 2 ) ra - (where m is an integer of from 1 to 7) or -0-(CH 2 )p- (where p is an integer of from 1 to 7) ;
  • the above-mentioned "5-membered or 6-membered heterocyclic ring” includes, for example, pyridine, pyrazine, pyrrole, thiophene, thiazole, tetrahydropyrazine, piperidine, etc.
  • Ring A includes heterocyclic rings of the above-mentioned formula (A-5), etc.
  • Ring B includes benzene rings of the above-mentioned formulae (B-7) and (B-8), especially the above-mentioned formula ( B- 10 ) , etc .
  • halogen atom includes, for example, fluorine, chlorine and bromine atoms, etc.
  • the "optionally-halogenated C ⁇ alkyl group” includes, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2, 2, 2-trifluoroethyl, perfluoroethyl, propyl, 3,3,3- trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4 ,4 , 4-trifluorobutyl, isobutyl, sec-butyl and tert-butyl groups, etc.; the "optionally halogenated C ⁇ alkyl group” includes pentyl and hexyl groups, etc. , in addition to the above-mentioned alkyl groups and halogenated alkyl groups.
  • the "optionally halogenated C x . 4 alkoxy group” includes, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2, 2, 2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, 4, 4 , 4-trifluorobutoxy, isobutoxy, sec-butoxy and tert-butoxy groups, etc.; and the "optionally halogenated C ⁇ alkoxy group” includes pentyloxy and hexyloxy groups , etc . , in addition to the above-mentioned alkoxy groups and halogenated alkoxy groups .
  • Ring A is a 5-membered or 6-membered heterocyclic ring having one nitrogen atom or one sulfur atom, in addition to carbon atoms , for example, a heterocyclic ring of a formula (A-7):
  • Ring B is a benzene ring optionally having 1 to 3 substituents selected from a halogen atom and an optionally halogenated C 1 . 4 alkyl group
  • Ring C is a benzene ring optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C 1 . 4 alkyl group and an optionally halogenated C 1 _ 4 alkoxy group
  • D that constitutes Ring Z is -(CH 2 ) m - (where m is an integer of from 1 to 7) or -0-(CH 2 )p- (where p is integer of from 1 to 7 ) ;
  • halogen atom the "optionally halogenated C ⁇ alkyl group” and the “optionally halogenated alkoxy group” , mentioned are those as referred to hereinabove for the foregoing compounds ( 1 ) .
  • R a and R b are the same or different and represent, independently, a hydrogen atom, optionally halogenated C ⁇ _ 4 alkyl groups, alkyl groups, alkyl groups, mono- or alkyl groups, C 3 - ⁇ o cycloalkylamino-Ci.g alkyl groups, C ⁇ alkyl groups having 5-membered or 6-membered cyclicamino which optionally substituted by C ⁇ alkyl, C ⁇ alkyl groups; or
  • R a and R b are bonded to each other to form pyridine ring which is optionally substituted by 1 to 3 substituents selected from a halogen atom and a C x . 4 alkyl group;
  • Ring B is a benzene ring optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C 1 . 4 alkyl group and an optionally halogenated C x _ 4 alkoxy group;
  • Ring C is a benzene ring optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C ⁇ X
  • alkyl group an optionally halogenated C 1 _ i alkoxy group, an amino group optionally substituted by C ⁇ alkyl group, a C 1.3 acyloxy group and a hydroxy group;
  • Preferred compounds of formulae (I) and (la) include, for example, compounds of the formula:
  • D and E represent alkylene groups optionally having an oxo group and the other symbols have the same meanings as above, or salts thereof.
  • D and E represent, independently, a C ⁇ alkylene group optionally substituted by one oxo group.
  • More preferred compounds of formulae (I) and (la) include, for example, compounds of the formula:
  • n represents an integer of from 1 to 7, and the other symbols have the same meanings as above or salts thereof.
  • m is preferably an integer of from 2 to 5.
  • R a and R b are the same or different and represent, independently, a hydrogen atom or a substituent selected from the group consisting of X
  • a 5-membered to 9-membered (preferably 6-membered) cyclicamino group which may have 1 to 3 hetero atoms (preferably 1 or 2 ) selected from the group consisting of nitrogen, oxygen and sulfur atoms, in addition to the nitrogen atom in the amino group and which may be substituted by Ci. s alkyl group,
  • Ring A is a 5-membered to 9-membered aromatic heterocyclic ring having from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, in addition to carbon atoms (preferably pyridine ring) , which may be substituted by C x _ 6 alkyl group;
  • the Ring B is a C 6 . 14 aryl group (preferably benzene ring) which may be substituted by substituents selected from the group consisting of (i) a C x _ 6 alkyl group optionally substituted by a hydroxy group, (ii) a carboxyl group and X
  • the Ring C is a C 6 . 14 aryl group (preferably benzene ring) which may be substituted by 1 to 3 substituents selected from the group consisting of (i) a halogen atom, (ii) optionally halogenated C ⁇ ,, alkyl group and (iii) C x _ 10 alkoxy grou ;
  • the Ring Z is a 5-membered to 12-membered heterocyclic ring optionally having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, in addition to Y and the nitrogen atom already on Ring Z, which may be substituted by 1 to 3 substituents selected from the group consisting of (i) a C 1 .
  • R 1 is a C 1 . 6 alkyl group
  • R 2 is a C ⁇ alkoxy group, optionally halogenated C x _ 6 alkyl group, a halogen atom, a hydroxy group or a C 7 .
  • X is 1 to 5 groups selected from the group consisting of a hydrogen atom, a C 1 _ 6 alkyl group and a halogen atom, provided that (1) when R 1 is a methyl group and R 2 is s trifluoromethyl group, X is a halogen atom and (2) when R 1 is a methyl group and R 2 is a methoxy group, X is a hydrogen atom or a halogen atom, is a novel compound.
  • the "C 1 _ 6 alkyl group” represented by R 1 , R 2 and X includes , for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl groups and so on, and preferably a C ⁇ _ 3 alkyl group such as methyl, ethyl and so on, and more preferably methyl.
  • the "halogen atom” which are substituents of the C x _ 6 alkyl group” represented by R 2 includes , for example, fluorine, chlorine, bromine and iodine atoms.
  • the halogen atom includes, for example, chlorine atom.
  • the "optionally halogenated C x , 6 alkyl group” includes, for example, trichloromethyl, trifluoromethyl and so on, and preferably the "optionally halogenated C ⁇ alkyl group” includes, for example, trifluoromethyl.
  • the "C 7 . 15 aralkyloxy group” represented by R 2 includes, for example, benzyloxy, phenylethyloxy and so on, and preferably the "C 7 . 15 aralkyloxy group” includes, for example, phenylethyloxy.
  • halogen atom represented by R 2 or X includes , for example, fluorine, chlorine, bromine and iodine atoms.
  • the halogen atom includes, for example, chlorine atom.
  • C,. 6 alkoxy group" represented by R 2 includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., preferably the alkoxy group" includes, for example, methoxy, ethoxy, isopropoxy, etc. , and more preferably the alkoxy group” includes , for example, methoxy.
  • the number of X which substitutes a phenyl group is 1 to 5.
  • X is a C ⁇ _ 6 alkyl group or a halogen atom
  • the number of them are usually 1 to 3 , preferably 1 or 2.
  • the position of substitution of X is not limited when X is a alkyl group or a halogen atom, for example, when the number is 1, 4-position of phenyl is preferred, and when the number is 2, 3- or 4-position of phenyl is preferred.
  • X are a halogen atom (particularly, a chlorine atom) and so on.
  • R 1 are a C ⁇ _ 3 alkyl group such as methyl, ethyl, propyl, isopropyl, etc., and more preferable examples are methyl, etc..
  • R 2 are a C _ 3 alkoxy group such as methoxy, ethoxy, isopropoxy, etc. , an optionally halogenated C 1 . 3 alkyl group such as methyl, trifluoromethyl, etc. , a halogen atom such as a chlorine atom, etc. , a hydroxy group or a benzyloxy group.
  • X are a hydrogen atom, a alkyl group such as methyl, etc.
  • halogen atoms such as a chlorine atom, a fluoro arom, etc.
  • (9R)-7-(3,5-dimethoxybenzyl) -5- ( 4- fluorophenyl)-6,7,8,9,10,ll-hexahydro-9-methyl-6,13- dioxo-13H- [l,4]diazocino[2, 1-g] [1, 7 ]naphthyridine is preferred.
  • the heterocyclic compounds ( I ) form salts and used in medicines , it is preferable that the salts are pharmaceutically-acceptable salts .
  • Such pharmaceutically-acceptable salts include salts with inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid, etc., or salts with organic acids, such as acetic acid, malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, palmitic acid, salicylic acid, stearic acid, etc.
  • inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid, etc.
  • organic acids such as acetic acid, malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, palmitic acid, salicylic acid
  • Heterocyclic compounds ( I ) or salts thereof include stereoisomers such as cis- and trans-isomers, etc., racemates, as well as optically-active forms such as R- forms, S-forms, etc.
  • the heterocyclic compounds (I) or salts thereof may include conformation-dependent isomers. All such isomers are within the scope of the heterocyclic compounds ( I ) or salts thereof. And, hydrate and non-hydrate are within the scope of the heterocyclic compounds (I) or salts thereof.
  • the pro-drugs of the compounds (I) or salts thereof means heterocyclic compounds which are converted to the heterocyclic compounds (I) or salts thereof under the physiological condition or with a reaction due to an enzyme, an gastric acid, etc. in the living body, that is, (i) compounds which are converted to the compounds ( I ) or salts thereof with oxidation, reduction, heterocyclic hydrolysis , etc. according to an enzyme; (ii) compounds which are converted to the heterocyclic compounds (I) or salts thereof with gastric acid, etc..
  • Examples of the pro-drug of the heterocyclic compounds (I) or salts thereof include compounds wherein amino groups of the heterocyclic compounds ( I ) are substituted with acyl, alkyl, phosphoric acid, etc. (e.g. compounds wherein amino groups of the the compounds (I) are substituted with eicosanoyl, alanyl, pentylaminocarbonyl , ( 5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl , tetrahydrofuranyl, pyrrolidylmethyl , pivaloyloxymethyl , tert-butyl, etc.); compounds wherein hydroxy groups of the heterocyclic compound (I) are substituted with acyl, alkyl, phosphoric acid, boric acid, etc.
  • heterocyclic compound (I) are modified with ester, amide, etc.
  • ester e.g. compounds wherein carboxyl groups of the compound (I) are modified with ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, ( 5-methyl-2-oxo-1 , 3-dioxolen-4- yl)methyl ester, cyclohexyloxycarbonylethyl ester, methyl amide, etc.); etc.
  • pro-drug can be produced by per se known method from the heterocyclic compounds ( I ) or salts thereof.
  • the pro-drugs of the heterocyclic compounds ( I ) or salts thereof may be compounds which are converted into the heterocyclic compounds (I) under the physiological conditions as described in "Pharmaceutical Research and Development", Vol.7 (Drug Design) , pages 163-198 published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan).
  • the heterocyclic compound ( I ) , the heterocyclic compound ( I ' ) or a salt thereof can be produced according to the method disclosed in EP-A-0733632, particularly working examples thereof, or an analogous method thereof.
  • heterocyclic compound (I 1 ) or salts thereof can be produced, for example, by cyclizing a compound of the formula (II): 0
  • D and E represent groups from which a group represented by the formula:
  • L represents a leaving group, and the other symbols are the same meanings as defined above, or a salt thereof.
  • the leaving group L in compound (II) includes, for example, a halogen atom (e.g., chlorine, bromine and iodine atoms, etc.), a substituted sulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy groups, etc.), etc.
  • the compound (II) can be applied to the reaction as a free compound but may also be applied thereto as its salt (for example, as an alkali metal salt, such as lithium, sodium, potassium or the like salt, of the compound).
  • the reaction is conducted in a solvent that is inert to the reaction.
  • the solvent for example, preferably used is any of halogenated hydrocarbons such as dichloromethane, chloroform, etc. , nitriles such as acetonitrile, etc., ethers such as dimethoxyethane , tetrahydrofuran, etc., aprotic polar solvents such as dimethylformamide , dimethylsulfoxide, hexamethylphosphoramide, etc.
  • a base for example, advantageously employed is any of inorganic bases (alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc . ; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; sodium amide; alkoxides such as sodium methoxide, sodium ethoxide, etc.
  • inorganic bases alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc .
  • alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, etc.
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.
  • alkali metal hydrides such as sodium hydride, potassium hydride, etc.
  • sodium amide alkoxides such as sodium methoxide, sodium ethoxide, etc.
  • organic bases amines such as trimethylamine , triethylamine , diisopropylethylamine, etc.; cyclic amines such as pyridine, etc.
  • a base for example, any of the above-mentioned alkali metal salts, alkaline earth metal salts, etc.
  • the amount of the base varies depending on the kind of the compound (II) and the solvent to be used and on the other reaction conditions, and is, in general, from 1 to 10 mols, preferably from 1 to 5 mols, per mol of the compound (II) used.
  • the reaction temperature falls, for example, within the range between about -50° C and about 200° C, preferably between about -20° C and about 150° C.
  • the reaction time varies depending on the kind of the compound (II) used or the kind of its salt used and also on the reaction temperature , etc., and is, for example, from 1 to 72 hours, preferably from 1 to 24 hours.
  • the starting compounds (II) can be produced according to the methods disclosed in EP-A-0733632.
  • heterocyclic compounds (I) or salts thereof have tachykinin receptor (especially SP and/or NKA receptor(s)) antagonistic activity, and have the function of inhibiting the tracheal plasma extravasation induced by capsaicin.
  • tachykinin receptor especially SP and/or NKA receptor(s)
  • Capsaicin (a main ingredient of the burning taste of red pepper) is known as a substance that liberates endogenous neuropeptides, such as SP, NKA and calcitonin gene-related peptide(CGRP) by stimulating C-fiber primary sensory nerve that contains such neuropeptides .
  • endogenous neuropeptides such as SP, NKA and calcitonin gene-related peptide(CGRP)
  • CGRP calcitonin gene-related peptide
  • the inhibitory action of the plasma extravasation of the heterocyclic compounds (I) or salt thereof is considered to be based on the antagonistic activity toward tachykinin receptor.
  • the heterocyclic compounds (I) or salts thereof are safe as having low toxicity.
  • heterocyclic compounds (I) or salts thereof are usable as safe medicines for preventing and treating depression, anxiety, manic- depressive illness or psychopathy in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, bovines, sheep, monkeys, man, etc.).
  • mammals e.g., mice, rats, hamsters, rabbits, cats, dogs, bovines, sheep, monkeys, man, etc.
  • heterocyclic compounds (I) or salts thereof are also usable as safe medicines for preventing and treating Down's syndrome, amyotrophic lateral aclerosis (ALS; Lou Gehring ' s disease), diabetic neuropathy, peripheral neuropathy, bronchoconvulsion, chronic obstructive plumonary disease (COPD), adverse immunological reactions such as rejection of transplanted tissues, plasma extravation induced by cytokines in chemotherapy, disturbances of blood flow by vasodilation and angina, fibrotissue inflammation, vernal conjunctitis , stimulation-indeced miosis, dry eye syndrome, proliferative vitreoretinopathy, eczema, urticaria, sunburn, atopic dermatitis, addiction disorders such as alcoholism, foods ataxia( inhibition of uptaking foods), stress-related somatic disorders, reflex sympathetic dystrophy such as shoulder/hand syndrome, systemic lupus erythematosus , fibrosis and collagen disease such as s
  • the heterocyclic compound (I' ) are also usable as safe medicines for preventing and treating inflammations or allergic disorders (e.g., atopy, dermatitis, herpes, proriasis, asthma, bronchitis, expectoration, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc.), pain, migraine, neuralgia, pruritus, cough, and additionally disorders of central nervous systems [e.g.
  • digestive diseases for example, irritable bowel syndrome (e.g., disorders of dejection such as diarrhea, constipation and mucous diarrhea; bellyache, distention of abdomen, etc.), ulcerative colitis, Crohn's disease, diseases caused by a spiral urease-positive gram-negative bacterium such as Helicobacter pylori, etc.), emesis (e.g., nausea, vomiturition, acute vomiting, delayed vomiting, retching,epidemic vomiting, fecal vomiting, morning vomiting, pernicious vomiting, vomiting of pregnancy, projectile vomiting, psychogenic vomiting, retention vomiting, etc.), disorders of micturition (for example, pollakisuria, urinary incontinence etc.), disturbances of circulation (for example, angina pectories, hypertension, cardiac insufficiency, thrombosis, etc.) and immunopathy, etc..
  • irritable bowel syndrome e.g., disorders of dejection such as diarrhea, constipation and mucous diarrhea; bellyache, distention
  • the compounds (I') or salts thereof are usable as a tachykinin receptor antagonist and as an ameliorative preparation for disorders of micturition such as pollakisuria urimary incontinence, etc., and even as medicines for treating such disorders of micturition.
  • compositions comprising heterocyclic compounds (I) or salts thereof of the present invention may be in any solid forms of powders , granules , tablets , capsules , etc., and in any liquid forms of syrups, emulsions, injections, etc.
  • the preventive and remedial compositions of the present invention can be produced by any conventional methods of. for example, blending, kneading, granulation, tabletting, coating, sterilization, emulsification, etc., in accordance with the forms of the preparations to be produced.
  • blending, kneading, granulation, tabletting, coating, sterilization, emulsification, etc. in accordance with the forms of the preparations to be produced.
  • referred to are the particular items in the general remarks for pharmaceutical preparations in the Japanese Pharmacopeia.
  • the content of the compounds or salts thereof is , though varying depending on the forms of the preparations , generally from 0.01 to 100 % by weight, preferably from 0.1 to 50 % by weight , more preferably from 0.5 to 20 % by weight , relative to the total weight of each preparation.
  • heterocyclic compounds ( I ) or salts thereof of the present invention are used in medicines such as those mentioned above, they are, either directly or after having been mixed with suitable, pharmaceutically-acceptable carriers, for example, vehicles (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, arable gum, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinyl pyrrolidone, etc.), lubricants
  • disintegrators e.g., calcium carboxymethyl cellulose , talc , etc .
  • diluents e.g. , water for injection, physiological saline, etc.
  • additives e.g., stabilizer, preservative, colorant, fragrance, dissolution aid, emulsifier, buffer, isotonic agent , etc.
  • the dose of the pharmaceutical composition of the present invention varies, depending on the kind of the heterocyclic compounds (I) or pharmaceutically- acceptable salts thereof, the administration route, the condition and the age of patients, etc.
  • the dose for oral administration of the pharmaceutical preparation to an adult patient suffering from depression is, in general, from about 0.005 to 50 mg/kg/day, preferably from about 0.05 to 10 mg/kg/day, more preferably from about 0.2 to 4 mg/kg/day, in terms of the heterocyclic compound ( I ) or its salt , which may be administered once a day or in two or three portions a day.
  • Other anti-depression agent, anti-anxiety agent, anti-manic-depressive illness, anti-psychopathy agent can be added into the pharmaceutical compositions of the present invention or can be used together with the heterocyclic compounds (I) or salts thereof.
  • the anti-depression agent are fluoxetine, sertraline, paroxetine and so on.
  • anti-anxiety agent examples include diazepam, buspirone, lorazepam, alprazolam and so on.
  • Examples of the anti-manic-depressive illness are lithium carbonate, sultopride, carbamazepine, levomepromazine and so on.
  • anti-psychopathy agent examples include risperidone, olanzapine, quetiapine and so on.
  • heterocyclic compounds (I) or salts thereof may be optionally blended with any desired amounts of any other pharmaceutically-active ingredients to formulate pharmaceutical compositions.
  • active ingredients include, for example, drugs for central nervous systems (e.g., imipramine, etc.), anti-cholinergic drugs (e.g., oxybutynin, etc.), ⁇ ⁇ receptor-blocking drugs (e.g., tamsulosin, etc.), muscle relaxants (e.g., baclofen, etc.), potassium channel-opening drugs (e.g., nicorandil, etc.), calcium channel-blocking drugs (e.g., nifedipine, etc.), etc.
  • drugs for central nervous systems e.g., imipramine, etc.
  • anti-cholinergic drugs e.g., oxybutynin, etc.
  • ⁇ ⁇ receptor-blocking drugs e.g., tamsulosin, etc.
  • muscle relaxants e.
  • the content of drugs other than the heterocyclic compounds (I) or salts thereof is, though varying depending on the forms of the preparations, generally from 0.01 to 80 % by weight, preferably from 0.1 to 50 % by weight, more preferably from 0.5 to 20 % by weight, relative to the total weight of each preparation.
  • Room temperature as referred to hereinunder generally means temperatures falling between about 10° C and about 35° C.
  • sodium sulfate or magnesium sulfate was used for dring the extract solutions.
  • Step 3 A mixture of the compound (0.86 g) as obtained in Step
  • 1,2-dichloroethane (3 ml) and THF (3 ml) was heated under reflux for 40 minutes, and then the solvent was removed by distillation.
  • a mixture of THF (5 ml), 3,5- bis( trifluoromethyl )benzylamine (82 mg), triethylamine (0.12 ml) and THF (2 ml) was added to the residue and stirred for 2 hours at room temperature.
  • Ethyl acetate was added to the reaction mixture , which was washed with water , diluted hydrochloric acid, aqueous sodium hydrogencarbonate and water in that order, and then dried. After the solvent was removed by distillation, the entitled compound was obtained X
  • Step 1 The compound as obtained in Step 1 was reacted with acetic acid and hydrochloric acid and treated in the same manner as in Step 2 in Reference Example 2 , to obtain
  • Step 4 The compound as obtained in Step 3 was reacted with 3-amino-l-propanol and treated in the same manner as in Reference Example 5, to obtain the entitled compound as colorless crystals, m.p. 129-130° C (recrystallized from ethyl acetate-ethyl ether)
  • Step 1 4-(4-Methylbenzoyl) -3-pyridinecarboxylic acid was used in place of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid in Step 1 in Reference Example 2 , reacted and treated in the same manner as in Step 1 in Reference Example 2, to obtain diethyl 3, 4-dihydro-4-hydroxy-4- (4- methylphenyl ) - 1-oxo- 1H-pyrano [ 3 , 4-c ]pyridine-3,3- X
  • Step 1 The compound as obtained in Step 1 was reacted with acetic acid and hydrochloric acid and treated in the same manner as in Step 2 in Reference Example 2 , to obtain 4- ( 4 -methylphenyl ) - 1-oxo-1H-pyrano [ 3 , 4-c ]pyridine-3- carboxylic acid as colorless crystals. m.p. 254-256° C (recrystallized from THF-isopropyl ether)
  • Step 4 The compound as obtained in Step 3 was reacted with
  • Step 1 N- ( 2-Aminoethyl) -N- [3,5- bis ( trifluoromethyl)benzyl] -2-chloro-4-phenyl-3- pyridinecarboxamide
  • Step 2 Thionyl chloride (0.15 ml) and DMF (catalytic amount) were added to a THF (5 ml) solution of 2-chloro-4- phenyl-3-pyridinecarboxylic acid ( 145 mg) and heated under reflux for 2 hours . The solvent was removed by distillation , and the residue was dissolved in THF (5 ml) .
  • N-[3,5- bis (trifluoromethyl)benzyl] -N' -tert- butoxycarbonylethylenediamine used herein was prepared as an oily compound, by reacting ethylenediamine with 3,5- bis( trifluoromethyl)benzyl methanesulfonate in THF to give an oily compound of N-[3,5- bis( trifluoromethyl)benzyl] ethylenediamine, followed by X
  • Step 1 The amine as obtained in Step 1 was used in place of N- [ 3 , 5-bis ( trifluoromethyl)benzyl] -N- ( 2- hydroxyethyl)amine in Step 2 in Reference Example 12 , reacted and treated in the same manner as in Step 2 in
  • the PH of the aqueous layer was adjusted to 2 - 3 by adding 2 N-hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated saline solution and dried, and the solvent was removed by distillation. Thus, obtained was 5-methyl-4-phenyl-2, 3-pyridinedicarboxylic acid as pale yellow crystals (3.06 g) . m.p.
  • Step 1 The compound as obtained in Step 1 was reacted and treated in the same manner as in Step 2 in Reference Example 33, to obtain a mixture of 2-ethyl ester and 3-ethyl ester
  • Step 4 The compound as obtained in Step 3 was reacted and treated in the same manner as in Step 4 in Reference Example
  • Example 33 was reacted with N-benzyl-N- ( 2- hydroxyethyl ) amine and treated in the same manner as in Step
  • Step 1 The compound as obtained in Step 1 was reacted and treated in the same manner as in Step 4 in Reference Example 33 to obtain the entitled compound as a pale-yellow, oily substance.
  • Step 2 Using the compound as obtained in Step 1 and 4- amino- 1-butanol, substantially the same reaction and work-up as Reference Example 13 was conducted to give the entitled compound as colorless crystals. m.p. 205-207° C (recrystallized from acetone-isopropyl ether)
  • Step 2 Starting from the compound as obtained in Step 1 and THP-ether of (R) -4-amino-2-methyl- 1-butanol, substantially the same reaction and work-up as Reference Example 19 was conducted to give the entitled compound as colorless crystals. m.p. 169-172° C (recrystallized from acetone-isopropyl ether)
  • Example 55 to obtain the entitled compound as colorless crystals. m.p. 192-193° C (recrystallized from ethyl acetate- isopropyl ether)
  • Example 55 to obtain the entitled compound as colorless crystals. m.p. 264-266° C (recrystallized from ethyl acetate-ethyl ether)
  • Example 55 to obtain the entitled compound as colorless crystals. m.p. 235-235° C (recrystallized from ethyl acetate)
  • Example 55 to obtain the entitled compound as colorless crystals. m.p. 244-245° C (recrystallized from ethyl acetate-THF- ethyl)
  • Example 66 to obtain the entitled compound as colorless crystals. m.p. 150-152° C (recrystallized from ethyl acetate- isopropyl ether)

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EP99909233A 1998-03-19 1999-03-18 Heterocyclic compounds, their production and use as tachykinin receptor antagonists Withdrawn EP1061926A2 (en)

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TWI287003B (en) * 2000-07-24 2007-09-21 Hoffmann La Roche 4-phenyl-pyridine derivatives
US20040023843A1 (en) * 2000-09-26 2004-02-05 Takayuki Doi Preventives/remedies for emotional disorders
CA2514547A1 (en) 2003-01-28 2004-08-12 Takeda Pharmaceutical Company Limited Receptor agonists
US20110136788A1 (en) 2008-08-07 2011-06-09 Minoru Maruyama Therapeutic agent for irritable bowel syndrome
PE20161372A1 (es) 2014-02-03 2017-01-08 Vitae Pharmaceuticals Inc Inhibidores de dihidropirrolopiridina de ror-gamma
UA118989C2 (uk) 2014-10-14 2019-04-10 Вітае Фармасьютікалс, Інк. Дигідропіролопіридинові інгібітори ror-гамма
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
EP3331876B1 (en) 2015-08-05 2020-10-07 Vitae Pharmaceuticals, LLC Modulators of ror-gamma
MA53943A (fr) 2015-11-20 2021-08-25 Vitae Pharmaceuticals Llc Modulateurs de ror-gamma
TW202220968A (zh) 2016-01-29 2022-06-01 美商維它藥物有限責任公司 ＲＯＲ－γ調節劑
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2019018975A1 (en) 2017-07-24 2019-01-31 Vitae Pharmaceuticals, Inc. INHIBITORS OF ROR GAMMA
CN111225914B (zh) 2017-07-24 2022-10-11 生命医药有限责任公司 RORγ的抑制剂

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